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Malleson et al.

Pediatric Rheumatology 2010, 8:27


http://www.ped-rheum.com/content/8/1/27

REVIEW

Open Access

Review for the generalist: The antinuclear


antibody test in children - When to use it and
what to do with a positive titer
Peter N Malleson1, Murray J Mackinnon2, Michaela Sailer-Hoeck3, Charles H Spencer4*

Abstract
The antinuclear antibody test (ANA) is a much overused test in pediatrics. The ANA does have a role in serologic
testing but it should be a very limited one. It is often ordered as a screening test for rheumatic illnesses in a primary care setting. However, since it has low specificity and sensitivity for most rheumatic and musculoskeletal illnesses in children, it should not be ordered as a screening test for non-specific complaints such as musculoskeletal
pain. It should only be used as a diagnostic test for children with probable Systemic Lupus Erythematosus (SLE) or
Mixed Connective Tissue Disease, (MCTD) and other possible overlap-like illnesses. Such children should have
developed definite signs and symptoms of a disease before the ANA is ordered. This review presents data supporting these conclusions and a review of the ANA literature in adults and children.
By limiting ANA testing, primary care providers can avoid needless venipuncture pain, unnecessary referrals, extra
medical expenses, and most importantly, significant parental anxieties. It is best not to do the ANA test in most
children but if it ordered and is positive in a low titer (<1:640), the results can be ignored if the child is otherwise
well and does not have other features of a systemic illness.
Background
Since the introduction of the indirect immunofluorescence (IF) test for antinuclear antibodies (ANA) by
Friou in 1957 [1], ordering an ANA appears to have
become a reflexive response to the question could this
patient have a rheumatic disease? What is the evidence
that ordering such tests is of any value, and what should
be done with a positive test?
The ANA test in health and disease

In diagnosing children with rheumatic disease, there are


no markers as of now that identify a risk factor for a
disease. Risk factors might allow primary prevention
(e.g., screening for high serum cholesterol) or secondary
prevention (e.g., detecting an illness before there are
signs and symptoms e.g. pap smears for cervical cancer).
In rheumatology only tertiary prevention is possible as
illness may be detected as early in the disease course as
possible in an effort to try and prevent the disease
* Correspondence: charles.spencer@nationwidechildrens.org
4
Section of Rheumatology, Nationwide Childrens Hospital, Ohio State
University, Columbus, OH, USA
Full list of author information is available at the end of the article

worsening and causing significant complications. Ideally


there should be a screening test for children with arthritis or other positive rheumatic physical findings with a
high specificity (test normal when someone does not
have the disease) and high sensitivity (test abnormal
when someone has the illness). A screening test should
allow early diagnosis compatible with primary or secondary prevention.
For children with arthritis, only a few diagnostic tests
are available (e.g., Lyme titer) and the ANA in particular
has very limited usefulness as a diagnostic test. To put it
another way, ideally a test should always be positive in
those with a disease, and always negative in those without a disease. This situation rarely if ever occurs, but to
be useful a test generally needs to have sensitivity and
specificity of at least 90%. That is, at least 9 out of 10
individuals with the disease will have a positive test, a
true positive, and 9 out of 10 individuals without the
disease will have a negative test. Unfortunately the ANA
test, whether performed by IF or by an enzyme linked
immunosorbent method (ELISA), fails to demonstrate
these test characteristics [2]. The ELISA particularly has
its problem with false positives.

2010 Malleson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Malleson et al. Pediatric Rheumatology 2010, 8:27


http://www.ped-rheum.com/content/8/1/27

Part of the problem is that the test is being used indiscriminately as part of a rheumatologic work-up or
rheumatology panel. No test can sensibly be expected
to be accurate in the diagnoses of diseases as different
as juvenile idiopathic arthritis (JIA), rheumatoid arthritis, SLE, MCTD, scleroderma, or the vasculitis diseases.
Yet, in practice, this is what often seems to be asked of
the ANA test. However, even if the test is used more
sensibly to address specific questions such as: does this
child with a rash and fever have lupus? or does this
child with a swollen knee have juvenile idiopathic arthritis (JIA)?, or is this child with JIA going to develop
uveitis? we would argue that the ANA test is simply
not accurate enough to answer even these questions.
ANA in healthy populations

A number of studies have looked at the frequency of


positive ANA tests in healthy individuals. A study by
Arroyave et al. in 1988 [3] screened sera from 241 normal children, testing for only IgG ANA, using both
mouse kidney and human epithelial cells (HEp-2 cells).
The study found a maximum positivity rate of only 2.0%
at the lowest dilutions. However, data from adult studies
have found much higher rates. In an adult study from
15 international laboratories using HEp-2 cells as substrate [4], ANA positive tests occurred in 31.7% of a
putatively normal population at a serum dilution of
1:40. Even at a dilution of 1:320, 3.3% of the sera were
positive. Interestingly the ANA frequency did not differ
significantly across the age range of 20-60 years. The
rate of ANA positivity among blood donors in Holland
was also quite high at 12.7%, with titers greater than
1:80 occurring in over 4% [5]. It is not clear why there
is such a low frequency of ANA positivity in children,
compared to the much higher frequency found in most
adult studies (of which only two of many are referenced
here). As ANA tests are usually performed on children
or adults with musculoskeletal or rheumatologic symptoms or signs, the frequency of ANA among clinic
populations is more pertinent to our discussion than the
situation in the normal population
ANA in clinic populations-ANA titers

Chudwin et al. in 1983 [6] evaluated the clinical and


laboratory findings in 138 children with a positive ANA
test. The authors interpreted the fact that two-thirds of
the patients had a specific connective tissue disease as
being indicative that the ANA test is useful. Yet the fact
that one third did not have a definitive inflammatory
disease indicates that the ANA test has a very high false
positivity rate.
We evaluated the results of all the ANA tests performed at British Columbias Childrens Hospital over a
5 year span [7]. We found that the ANA test was

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positive at a titer of 1:20 or greater in 41% of all sera


tested, and in 65% of all patients in whom a diagnosis
could be obtained from the ordering physician. The frequency was the same for those children with or without
a diagnosis of a rheumatic disease. At a screening serum
dilution of 1:40 a positive test had a sensitivity of only
63% and a positive predictive value (the frequency that a
positive test is indicative of disease) of only 33% for any
rheumatic disease.
For SLE, MCTD or overlap syndrome, the ANA had a
very high sensitivity of 98%, but a very low positive predictive rate of only 10%. Positive and negative predictive
values are affected by the prevalence of the disease
being tested. Therefore one might expect somewhat better predictive values from a pediatric rheumatology
clinic than from a wide population of ill children. We
concluded from this study that although a negative
ANA test made the diagnosis of SLE or MCTD extremely unlikely, a positive test at even moderately high
titers of 1:160 has little or no diagnostic value [7].
ANA immunofluorescent staining

As our laboratory also provided information on the patterns of immunofluorescent staining, we have also been
able to evaluate what further use this information might
provide (previously unpublished data). Of 1369 individual patients sera tested, 445 were ANA positive in children with a known diagnosis. Of these children, 135 had
a rheumatic disease (juvenile rheumatoid arthritis (JRA)
(now known as JIA-the terms are used interchangeably
here), SLE, MCTD, or juvenile dermatomyositis (JDM)
but 310 had no convincing evidence of having a rheumatic disease.
Homogeneous, mitotic staining patterns were seen
much more commonly in children with a rheumatic disease than those without (p = 0.001). Interestingly, a
nucleolar pattern of staining was seen more commonly
in children without a rheumatic disease (p = 0.03). This
lack of an association of the nucleolar pattern in children with scleroderma specifically, and rheumatic disease in general has been commented on previously [8,9].
In our lab, no combination of ANA titer, or staining
pattern was specific for any particular rheumatic disease.
The test combinations with the best positive predictive
values for a rheumatic disease were: a) a titer 1:640
with mitotic positive staining or b) a titer 1:640 with a
homogenous and mitotic staining pattern. These tests
had positive predictive values of 77% and 72% respectively. Yet these results were only slightly higher than
the positive predictive value of 69% obtained with a titer
of 1:640 alone, ignoring the pattern of staining.
Although the addition of patterns somewhat increases
the specificity and positive predictive value of the ANA
test for a rheumatic disease, it does so at the expense of

Malleson et al. Pediatric Rheumatology 2010, 8:27


http://www.ped-rheum.com/content/8/1/27

both the sensitivity and negative predictive value of the


test using titers alone.
The pattern of staining also does not appear to be
helpful in distinguishing between rheumatic diseases.
For example, although high titer homogenous, mitotic
positive staining was the most common combination
seen in children with SLE, it was actually found in only
27.3% of ANA positive lupus patients. This combination
was also found in 12.5% of ANA positive JRA and 5.4%
of ANA positive JDM patients. This lack of specificity of
the ANA immunofluorescent pattern has been recognized previously, both for adults and children [8,10,11].
A study by Parker et al. [11] evaluated the usefulness of
combining ANA titer and pattern. Although they felt
that knowledge of both titer and pattern was helpful,
they did not calculate specific test characteristics, and in
fact no combination was restricted to any single rheumatic disease. Our assessment of these data is that the
addition of information about patterns of immunofluorescence does not appear to significantly improve the utility of the ANA test.
Practical Concerns about ANA Testing
Referrals for positive ANA titers

As part of a study exploring what precipitated a referral


to a pediatric rheumatologist, McGhee et al. [12] found
that children referred, at least in part, because of a positive ANA test were no more likely to have a chronic
inflammatory disease than children with a negative test.
In another study from a pediatric rheumatology clinic,
only 55% of all of the children with a positive ANA test
had an inflammatory rheumatic disease. Positive antibodies to double-stranded DNA or to extractable nuclear
antigens (Sm, RNP) indicating SLE or MCTD were
strongly correlated with an ANA titer 1:640. The
authors recommended therefore, that these more specific tests be performed only if the child had a positive
ANA test at high titer [13].
McGhee and colleagues reviewed the ANA titer clinical utility in 2004 [14]. One hundred and ten children
were evaluated who had been referred for a positive
ANA. Of the 110, 10 subsequently were found to have
SLE, 18 had JRA, 1 had MCTD, and 1 had Raynauds
phenomenon. Neither a positive ANA neither titer nor
the degree of positivity of the ANA helped pick out the
children with SLE from the children without a chronic
inflammatory disease. Tellingly, it wasnt the elevated
ANA titer that distinguished the children with JRA from
those with other musculoskeletal problems, but the history (e.g., morning stiffness) and the physical exam (e.g.,
presence of rash, swollen joints).
All these studies demonstrate that a positive ANA test
is found frequently in a pediatric hospital population,
and even in high titer has only a poor ability to

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determine whether a child has an inflammatory rheumatic disease.


Development of rheumatic diseases in ANA positive
individuals

It could be argued that the finding of a positive ANA


test indicates that the child has an occult disease that
will become manifest later. Is there any evidence to support or refute this?
There is some evidence that ANA may sometimes precede the development of SLE by several years. Using
Finlands Social Security Institutions population registry,
Aho et al. [15] were able to trace 16 serum samples from
apparently healthy subjects who later developed SLE or
MCTD. Ten of the 16 (62.5%) samples were positive for
ANA. Eight of the 11 (72.7%) were positive when the interval from sampling to onset of first symptoms was 2 years
and 2 of 5 cases (40%) were positive when the interval
was > 3 years. Based on an incidence rate of lupus of
5/100,000/year, the authors calculated that lupus would
develop in less than one percent of the ANA positive individuals. Cabral et al. [16] followed the course of 24 children
who were considered clinically not to have an inflammatory disease despite being ANA positive and found that no
patient developed an overt inflammatory disease during a
follow-up period of 61 months (range 13 to 138 months).
Some studies have evaluated the outcome in patients
with fibromyalgia. Fibromyalgia is a musculoskeletal
pain condition not thought to be an autoimmune disease. Interestingly, some fibromyalgia patients are also
ANA positive, but there has been no evidence that the
occurrence of a positive ANA influences patient outcome. Al-Allaf et al. [17] found the ANA positivity rate
(titers not given, a positive result was simply defined as
plus) in their adult patients with fibromyalgia was
8.8%. This rate was almost identical to the 8.9% ANA
positivity rate in their control patients with osteoarthritis. The 12 individuals who had fibromyalgia and were
ANA positive were matched for age and sex with 12
ANA negative patients. Over a 2-4 year follow-up period
one patient in the ANA positive group fulfilled criteria
for SLE, and one in the ANA negative group fulfilled
criteria for Sjgrens syndrome. The authors concluded
that the ANA test (at least in low titer) was not a good
predictor of future connective tissue disease.
In a separate study of 59 pediatric patients with fibromyalgia, 17 (28.8%) were ANA positive (mean titer 1:160).
Fifty patients were followed for a mean of 18.3 months
and during that time no patient developed a connective
tissue disease [18]. We would conclude from these findings that only rarely is the presence of ANA the harbinger
of occult SLE or another connective tissue disease.
ANA and other diseases

It should also be remembered that ANA are associated


not only with the classical autoimmune diseases, but

Malleson et al. Pediatric Rheumatology 2010, 8:27


http://www.ped-rheum.com/content/8/1/27

Table 1 Diseases or syndromes that are frequently


associated with an positive ANA test
Rheumatic

Non-rheumatic

Juvenile rheumatoid arthritis

Infection-(e.g., viral, Lyme)

Psoriatic arthritis

Malignancy (e.g., ALL)

Systemic lupus erythematosus


Systemic lupus erythematosus

Environmental toxins
Drugs

Juvenile dermatomyositis
Mixed Connective Tissue Disease
Drug-induced lupus syndrome
Abbreviations ALL acute lymphocytic leukemia

also with infection [19], malignancy [20,21] and drugs


(Table 1) [22]. To illustrate this point, a study of Jones
et al in 2006 analyzed 71 children who presented to a
rheumatologist and who eventually were diagnosed with
acute lymphocytic leukemia. Of the 71 children, 47 were
tested for the ANA titer performed upon referral. Of
the 47 ALL children, 8 (17%) had an elevated ANA titer
[21]. Not only is the ANA test often positive in nonrheumatic diseases, it is often negative in many rheumatic diseases (Table 2).
Environmental toxins may also predispose to ANA
production. Although hopefully not relevant in pediatrics, there is evidence of an increased frequency of
ANA in individuals with silicone breast implants [23],
and at least two studies have suggested that rural populations have a higher frequency of ANA positivity than
urban populations, perhaps due to toxin exposure
[24,25]. Therefore the finding of a positive ANA test
should not blind the physician to the possibility of a
non-autoimmune diagnosis.
A situation where a positive ANA test may be of
some value is in children diagnosed with idiopathic
Table 2 ANA positivity in rheumatic diseases in children
Diseases with ANA positivity

Diseases without ANA


positivity

Systemic lupus erythematosus

Systemic onset JIA

Juvenile idiopathic arthritis (excluding


enthesitis-related arthritis)

Rheumatic fever

Juvenile dermatomyositis

Post-streptococcal
arthritis

Scleroderma-systemic and local

Enthesitis-related
arthritis

Mixed Connective Tissue Disease

Reactive arthritis
syndromes
Henoch-Schnlein
purpura
Kawasaki disease
Other vasculitis
syndromes
Sarcoidosis

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thrombocytopenic purpura (ITP). In a study of 87 children with ITP, it was found that 36% of those with a
positive ANA (titer 1:40) developed further autoimmune symptoms. Five children developed SLE, compared to none of those who were ANA negative (p <
0.001). [26]
ANA positivity as a risk factor for uveitis in children with
JIA

There is little doubt that in children with JIA the ANA


test is more frequently positive in those with uveitis
than in children without uveitis. The American Academy of Pediatrics recommends performing the ANA test
as part of the screen for uveitis [27]. However, although
there is a statistically significant difference between children with and without uveitis, we would argue that this
difference itself is of little clinical significance.
In a recent study from Finland [28], for example, uveitis was found in 104 of 426 new cases of juvenile idiopathic arthritis. Antinuclear antibodies were found in
66% of those with uveitis compared to 37% of those
without uveitis, a statistically significant difference.
However if the presence or absence of a positive ANA
test was used in determining the frequency of ophthalmologic examinations, it is possible that some of the 46/
104 children with uveitis and negative ANAs might well
have had a delayed diagnosis due to the partial reliance
on the ANA positivity to determine the frequency of eye
checkups. So there is risk for ANA negative children as
well. This should not detract from the utility of a positive ANA in selecting out a population of children with
arthritis who are at a higher risk for uveitis.
What should be done?

So what should be done with a positive ANA test? Our


answer would be exemplified by the answer a local inhabitant gave when asked directions from place A to B by
a foreign tourist: I wouldnt be leaving from here! In
other words, it would be best if the ANA test had not
been done in the first place! We would suggest that a
positive ANA test can safely be ignored unless there are
other suggestive clinical signs, and simple laboratory
tests (such as a raised ESR or cytopenias) that point
towards a diagnosis of lupus or similar connective tissue
disease, particularly if the ANA titer is less than 1:640.
Given the high false positive rate of ANA tests, a positive test cannot be used as confirmatory evidence that
the child with a swollen joint has JIA, rather than some
other serious condition such as septic arthritis, leukemia,
or hemophilia. Similarly, symptoms such as fatigue and
aches and pains in a child should not be ascribed to SLE
simply because of a positive ANA test. It is much more
likely that such a child has an idiopathic pain syndrome
such as fibromyalgia or hypermobility. A negative ANA
test is more useful than a positive one, as it does, for all
practical purposes, exclude the diagnosis of SLE in a child.

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What is needed is a cost-effectiveness study to evaluate whether the ANA test should be replaced by testing
initially for anti-dsDNA and anti-ENA (anti-Sm, RNP,
SSA and SSB) antibodies. Until that study is done, we
would recommend that non-rheumatologists only do an
ANA test if there is a fairly high probability (perhaps a
10+% chance) that a childs symptoms could be due to
SLE or MCTD. If the test is positive at a titer of > 1:160
then it would be appropriate to order antibodies to
dsDNA and ENA, with lower titers being ignored as
well as complement levels.
We would strongly recommend that the ANA test is
not ordered indiscriminately as part of a rheumatologic
work-up. This is not a new message. Other pediatric
rheumatologists have pointed out in the literature that
the ANA is a poor screening test and is being used
inappropriately [7,9,12,14,16,29,30]. It is our hope that a
continued demonstration of these facts will gradually
decrease its inappropriate use. The cost of inappropriate
referrals, extra venipuncture, unnecessary expense, and
increased parental and child anxiety is a considerable
problem that pediatric rheumatologists see every day.

Conclusion
The question why the ANA test is so frequently positive
in populations without an autoimmune disease remains
a fascinating one. It suggests that the breaking of immunological tolerance is really quite common, but that this
tolerance breakdown only rarely leads to disease. It is
possible that antinuclear antibodies have some useful
function that is not yet fully understood.
However, the ANA test has such a high false-positivity
rate that a positive test is of little, if any, clinical utility
as a screening test and should not be ordered routinely
to screen children with musculoskeletal complaints. Its
use should be limited to the diagnosis of SLE, MCTD,
and similar systemic illnesses. If the test is performed,
low titer ANA results (< 1:640) in most cases should be
ignored unless the child is systemically ill and shows
signs of SLE or a similar systemic disease.
Abbreviations
ANA: antinuclear antibody titer; SLE or lupus: systemic lupus erythematosus;
HEp-2 cells: human epithelial cells used as ANA substrate; ENA: extranuclear
antigens; MCTD: mixed connective tissue disease; JRA: juvenile rheumatoid
arthritis; [(JIA): also known as juvenile idiopathic arthritis]; JDM: juvenile
dermatomyositis; dsDNA: double stranded DNA antibodies; Sm: Smith
antigen (one of the extractable nuclear antigens); RNP: ribonuclear protein
antigen; (another of the extractable nuclear antigens): SSA: Sjgrens
syndrome A antigen; (Ro): (one more of the extractable nuclear antigens);
SSB: Sjgrens syndrome B antigen; (La): (another of the extractable nuclear
antigens); ITP: idiopathic thrombocytopenic purpura; (JRA): juvenile
rheumatoid arthritis; (JIA): and juvenile idiopathic arthritis are the old and
new classification terms for chronic arthritis diseases in children. JRA is used
preferentially here as the data collection began before the term JIA was
more universally accepted.

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Acknowledgements
We would like to acknowledge the help of Louis Wadsworth MBBS, FRCPC,
Director, Hematopathology Program British Columbias Childrens Hospital
who provided generous help with acquiring the ANA data presented here.
Author details
1
Division of Rheumatology, University of British Columbia, Vancouver,
Canada. 2British Columbia Cancer Agency, Vancouver, Canada. 3Clinical
Department of Pediatrics, Clinical Division of General Pediatrics, Medical
University of Innsbruck, Innsbruck, Austria. 4Section of Rheumatology,
Nationwide Childrens Hospital, Ohio State University, Columbus, OH, USA.
Authors contributions
PM conceived the project, acquired the data, and reviewed the results; MM
did the statistical analyses. PM, MSH, and CHS were responsible for the
interpretation of the data and literature as well as preparation of the
manuscript. The final manuscript was approved by the authors.
Competing interests
The authors declare that they have no competing interests.
Received: 28 June 2010 Accepted: 20 October 2010
Published: 20 October 2010
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doi:10.1186/1546-0096-8-27
Cite this article as: Malleson et al.: Review for the generalist: The
antinuclear antibody test in children - When to use it and what to do
with a positive titer. Pediatric Rheumatology 2010 8:27.

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